Rapid disperse dosage form containing levetiracetam

ABSTRACT

A high dose rapidly dispersing three-dimensionally printed dosage form comprising a high dose of levetiracetam in a porous matrix that disperses in water within a period of less than about 10 seconds is disclosed. Also disclosed are methods of preparing the dosage form and of treating a condition, disease or disorder that is therapeutically responsive to levetiracetam.

CROSS-REFERENCE TO EARLIER FILED APPLICATIONS

The present application is a continuation of and claims the benefit ofPCT International Application No. PCT/US2014/028954 filed Mar. 14, 2014,which claims the benefit of U.S. Provisional Application No. 61/791,444filed Mar. 15, 2013, the entire disclosures of which are herebyincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to a rapidly dispersing (orodispersible)dosage form of levetiracetam. In particular, the dosage form disperseswithin a period of less than about fifteen seconds when placed in themouth of subject. The invention also relates to methods of use of thedosage form for the treatment of diseases, disorders or conditions thatare therapeutically responsive to levetiracetam. A process for preparingthe dosage form is also provided.

BACKGROUND OF THE INVENTION

Solid oral dosage forms containing levetiracetam (LEV;(S)-2-(2-oxopyrrolidin-1-yl)butanamide;(−)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide; described in U.S. Pat.No. 4,943,639) are known (FDA Electronic Orange Book). Solid tablets arecurrently available under the trademark KEPPRA® (NDA N021035, UCB, Inc.,approval date Nov. 30, 1999; package insert available athttp://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=9870). Thesetablets are known to contain 250, 500, 750 or 1000 mg of levetiracetamand the following excipients (inactive ingredients): colloidal silicondioxide, croscarmellose sodium, magnesium stearate, polyethylene glycol3350, polyethylene glycol 6000, polyvinyl alcohol, talc, titaniumdioxide, and additional agents listed below: 250 mg tablets contain FD&CBlue #2/indigo carmine aluminum lake; 500 mg tablets contain iron oxideyellow; 750 mg tablets contain FD&C yellow #6/sunset yellow FCF aluminumlake, iron oxide red. KEPPRA® oral solution dosage form is alsoavailable.

Levetiracetam is very soluble in water (104.0 g/100 mL). It is freelysoluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL),soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile(5.7 g/100 mL) and practically insoluble in n-hexane.

LEV has been found to be chemically stable in a wide range ofpharmaceutical formulations. Ingredients included in commerciallyavailable tablets of LEV include corn starch, croscarmellose sodium,povidone, colloidal silicon dioxide, talc, magnesium stearate,polyethylene glycol, titanium dioxide, iron oxide and polyvinyl alcohol,among others. However, under accelerated (60° C.) conditions of stress(acidic, alkaline, aqueous, oxidative, thermal or photo), it has beendemonstrated that LEV undergoes substantial degradation (Shah, DerPharmacia Sinica (2012), 3(5), 576-589). Shah reports that the rateconstant for oxidative degradation is smaller than for acidichydrolysis, base hydrolysis, water hydrolysis and UV photolysis.Prohotsky et al. (Am. J. Health Syst. Pharm. (2014), 71(3), 219-22)disclose the results of a study on the stability of an oral solution oflevetiracetam. They conclude that the solution is stable for up to sixmonths.

Ensom et al. (Can. J. Hosp. Pharm. (2011), 64(3), 207-211) disclose theresults of a study on the stability of extemporaneously compoundedsolutions of levetiracetam in ORA-SWEET and ORA-PLUS. They report thatall samples were unchanged over a period of at least 91 days.

LEV is indicated for treating epilepsy, as adjunctive treatment ofpartial onset seizures in adults and children 4 years of age and olderwith epilepsy, as adjunctive therapy in the treatment of myoclonicseizures in adults and adolescents 12 years of age and older withjuvenile myoclonic epilepsy, and as adjunctive therapy in the treatmentof primary generalized tonic-clonic seizures in adults and children 6years of age and older with idiopathic generalized epilepsy. It has alsobeen suggested for improving cognitive function in subjects that exhibitage-related cognitive impairment or are at risk thereof, includingsubjects having or at risk for Mild Cognitive Impairment (MCI),Age-related Cognitive Decline (ARCD) or Age-Associated Memory Impairment(AAMI).

LEV is dosed at high levels such as 250-1000 mg per tablet for thetreatment of epilepsy and seizures. Treatment is initiated with a dailydose of 1000 mg/day, given as twice-daily dosing (500 mg BID).Additional dosing increments may be given (1000 mg/day additional every2 weeks) to a maximum recommended daily dose of 3000 mg. Doses greaterthan 3000 mg/day have been used in open-label studies for periods of 6months and longer. However, young and elderly patients typicallyexperience difficulty in swallowing solid oral dosage forms containingsuch high doses, especially because of the large amount of excipientsincluded in known dosage forms. Difficulty in swallowing leads to poorpatient compliance. Attempts to resolve this problem have lead to thedevelopment of oral liquid and injectable formulations. Stability,contamination and inaccurate dosing problems, however, are stillassociated with such dosage forms.

Given the high doses of LEV required per tablet, it is difficult toformulate rapidly dispersible solid oral dosage forms with sufficienthardness and friability suitable for storage and handling. Attempts toresolve such problems are disclosed. U.S. Pat. No. 8,187,635 to Karavaset al. discloses tablets that contain dicalcium phosphate anddisintegrate in about 30 min WO 2007/012439 to UCB Pharma, S.A.discloses tablets that disintegrate in about 15-45 min WO 2006/102750 toGenpharm Inc. discloses tablets that are made by granulation andfluid-bed drying and disintegrate in about 3 to 8 min. Such tablets donot meet the U.S. F.D.A. requirements of an orodispersible dosage form.

Orodispersible dosage forms disperse or disintegrate in the mouth in aminimal amount of saliva or water. Such dosage forms provide ease ofswallowing, accuracy of dosing, and rapid therapeutic action. U.S. Pat.No. 7,749,533 to Fu et al. discloses a dosage form containing granulescontaining a drug, porous plastic substance, water penetration enhancer,binder and drug. The granules must be compressed in order to create thedosage form. U.S. Pat. No. 4,371,516 to Gregory et al. and U.S. Pat. No.5,738,875 disclose freeze-dried dosage forms. U.S. Pat. No. 5,178,878 toWehling et al. discloses a soft-compress orodispersible dosage form.Effervescent dosage forms and quick release coatings of insolublemicroparticles are described in U.S. Pat. Nos. 5,578,322 and 5,607,697.Freeze dried foams and liquids are described in U.S. Pat. No. 4,642,903and U.S. Pat. No. 5,631,023. Melt-spun dosage forms are described inU.S. Pat. Nos. 4,855,326, 5,380,473 and 5,518,730. U.S. 20070218129discloses an immediate release dispersible and orodispersible solidpharmaceutical composition having the form of particles with a sizelower than 710 μm upon dispersion into water, wherein the formulation ismade by wet granulation; however, the disintegration times range from 53to 60 sec.

U.S. Pat. No. 6,471,992, U.S. 2012-0207929 and U.S. 2003-0133975disclose three-dimensionally printed rapidly dispersing dosage forms.Even so, an orodispersible three-dimensionally printed dosage formcontaining LEV has not been suggested. It is not possible to predict apriori whether a three-dimensionally printed dosage form containingsubstantial amounts of LEV can be made to disperse in a minimal amountof aqueous fluid in 15 sec or less 10 sec or less or 5 sec or less whileat the same time possessing sufficient hardness to endure handling andstorage.

None of the above discloses a rapidly dissolving solid oral dosage formcontaining levetiracetam. WO 2011/136751 to Mahmut discloses acompressed effervescent tablet made from a granulate containing LEV;however, the tablet dissolves in about five minutes or less.CN102085194A to Beijing Yiling Bioengineering Co. Ltd. discloses anorally distintegrating freeze-dried dosage form containing LEV, PEG 600,maltodextrin and hydrolyzed gelatin. Freeze-dried dosage forms, however,are physically very unstable and exhibit extremely high friability sincethey are not hard.

The use of glycerin in the manufacture of a three-dimensionally printedarticle is disclosed in U.S. 20080281019, U.S. 20080187711, U.S.20070168815, U.S. 20040187714, U.S. 20030207959, U.S. 20070146734, U.S.20050197431, U.S. 20040056378, U.S. Pat. No. 5,902,441, U.S. Pat. No.6,416,850, and U.S. Pat. No. 6,838,035. There is no prior disclosure ofthe use of glycerin in the manufacture of a three-dimensionally printedrapidly dispersible dosage form.

It would be beneficial to provide a rapidly-dispersing orodispersiblesolid oral dosage form containing levetiracetam that exhibits lowfriability and sufficient hardness to withstand storage and handlingwhile at the same time exhibiting an extremely rapid disintegrationrate; however, no such suitable dosage form containing LEV has beendisclosed in the art.

SUMMARY OF THE INVENTION

The present invention seeks to overcome some or all of the disadvantagesinherent in the art. The present invention provides an orodispersiblesolid dosage form, as described herein, comprising levetiracetam as theprimary or sole active ingredient, wherein the dosage form comprises abound matrix that disperses in about 15 sec or less in a volume of about10 ml or less of water or saliva. The matrix disperses in the mouth of asubject to which it is administered, thereby facilitating swallowing andadministration. It would be a substantial improvement in the art toprovide an orodispersible solid dosage form, as described herein,comprising levetiracetam as the primary or sole active ingredient,wherein the dosage form comprises a bound matrix that disperses in 20sec or less in a volume of 5 ml or less of water or saliva. The matrixvery rapidly disperses in the mouth of a subject to which it isadministered, thereby facilitating swallowing and administration.

The dosage form is self-preserved and does not require the addition of apreservative, even though a preservative can be included if desired.Accordingly, some embodiments of the invention provide apreservative-free rapidly orodispersible dosage of LEV.

The inventors have discovered that levetiracetam undergoes oxidativedegradation during formulation by three-dimensional printing; however,no degradation products corresponding to acid-catalyzed orbased-catalyzed hydrolysis or photolytic or thermolytic degradation wereobserved. These results are surprising because (Shah, supra) teachesthat oxidative degradation of LEV occurs at a much slower rate thanhydrolysis or photolysis under accelerated conditions. The inventorshave discovered that inclusion of an antioxidant in the orodispersibledosage form of the invention provides protection against oxidativedegradation of LEV during manufacture and storage of the 3DPorodispersible dosage form. The inventors have succeeded in preparing a3DP orodispersible dosage form comprising LEV, wherein the content ofany individual oxidative degradant in the dosage form is less than 0.1%wt based upon the weight of LEV in the dosage form, wherein the dosageform comprises LEV, antioxidant, and water soluble binder comprisingperoxide as impurity. The content of any individual oxidative degradantremains at or below 0.1% wt even after storage at 21° C. for six monthsat 75% RH.

Accordingly, some embodiments of the invention provide a stable rapidlyorodispersible three-dimensionally printed solid porous matrixcomprising LEV, antioxidant, disintegrant and binder, wherein the matrixis stable to oxidative degradation of LEV when stored at 21° C. for sixmonths at 75% RH. The invention also provides a stable rapidlyorodispersible three-dimensionally printed solid porous matrixcomprising LEV, antioxidant, disintegrant and binder, wherein the matrixcomprises 0.1% or less of an oxidative degradant of LEV after beingstored at 21° C. for six months at 75% RH. In some embodiments, theantioxidant is selected from the group consisting of butylatedhydroxyanisole (BHA), butylated hydroxytoluene, sodium sulfite, sodiumbisulfite, methionine, vitamin E, or combinations thereof.

In some aspects, the invention provides a rapidly dispersible, i.e.orodispersible, dosage form and administration thereof for the treatmentof diseases, conditions or disorders that are therapeutically responsiveto levetiracetam. The rapidly dispersible solid dosage form comprises athree-dimensionally printed matrix comprising LEV, antioxidant and bulkmaterial. The matrix is formed by deposition of a printing fluid to apowder, whereby the particles of the powder become bound by LEV and/orbinder. The matrix is porous with a defined overall bulk density,disintegration (dispersion) time in aqueous fluid, dissolution time inaqueous fluid, and moisture content. The matrix provides a balance ofimproved chemical stability, sufficient hardness, low friability andextremely rapid dispersion time in a small volume of aqueous liquid.

Increasing the content of many different types of water solubleexcipients in the 3DP orodispersible dosage form generally results inincreased hardness and increased dispersion time. For example,increasing the content of water soluble binder and LEV results inincreased hardness and dispersion time. The inventors have discoveredthat increasing the content of glycerin in the 3DP dosage form increaseshardness but unexpectedly decreases dispersion time.

Accordingly, another aspect of the invention provides use of a printingfluid comprising glycerin and at least one pharmaceutically acceptablesolvent for the manufacture of a rapidly dispersible dosage form. Theinvention also provides a three-dimensional printing system comprising aglycerin-containing printing fluid, and provides a method ofthree-dimensionally printing an orodispersible dosage form, the methodcomprising: a) depositing an incremental layer of drug-containing powderonto a surface; b) depositing a sufficient amount of printing fluid ontothe incremental layer to bind particles in the powder, wherein theprinting fluid comprises glycerin and at least one pharmaceuticallyacceptable solvent; and c) repeating a) and b) thereby forming a rapidlyorodispersible.

Some embodiments of the invention include those wherein: a) the drug iswater soluble drug; b) the powder and/or printing fluid comprises watersoluble binder; c) the content of glycerin in the printing fluid rangesfrom >0% to 20% wt or about 0.05% to about 10% wt or about 0.05% toabout 5% wt; and/or d) the content of glycerin in the dosage form rangesfrom about 0.05%-3%, or about 0.1%-2%, or 0.5%-1.0% wt based upon finalweight of the dosage form.

Some aspects of the invention provide an orodispersible solid dosageform comprising a three-dimensionally printed porous matrix comprisingbound particles of LEV and bulk material, wherein the particles arebound by LEV and/or binder. The invention also provides anorodispersible dosage form comprising a three-dimensionally printedmatrix comprising bound particles of LEV, disintegrant, binder, andantioxidant, wherein the particles are bound by LEV and/or binder.

In some embodiments, LEV is present in crystalline form. All polymorphsthereof are contemplated. The crystallinity of LEV or any other materialcan be determined by differential scanning calorimetry (DSC) todetermine the presence of amorphous material. In some embodiments, LEVis present in amorphous form in the bulk powder or in the matrix

Embodiments of the invention include those wherein: a) the dosage formis not compressed; b) the matrix is not compressed; c) the hardness ofthe exterior surfaces of the dosage form is greater than the hardness ofan interior portion (one or more interior incremental printed layersthereof) of the dosage form, i.e. the exterior of the dosage form isharder than the interior; d) the dissolution time of LEV is slower thanthe dispersion time of the matrix when placed in an aqueous fluid; e)the matrix disperses in about 10 seconds or less when placed in a smallvolume of aqueous fluid; f) at least 75%, at least about 90, or at leastabout 95% of the LEV dissolves in about 2 minutes or less when placed inan aqueous fluid; g) LEV is present in a form selected from the groupconsisting of hydrate, hemi-hydrate, crystalline, amorphous, anhydrateor a combination thereof; h) the dosage form comprises not more than 10%wt and not less 0.1% moisture as determined by loss on drying at 120°C.; i) the hardness of the matrix is substantially uniform; j) thedosage form comprises one or more other medicaments; and/or k) acombination thereof.

The invention also provides a three-dimensionally printed orodispersibledosage form comprising a three-dimensionally printed orodispersiblematrix of bound particles, the matrix comprising LEV, disintegrant, oneor more binders, one or more surfactants, one or more antioxidants,glycerin and optionally one or more of the following: one or moreglidants (free-flow additive), one or more flavorants, one or morepreservatives; wherein, the matrix comprises particles bound by binderand LEV; the matrix is porous and non-compressed; the matrix dispersesin less than 15 sec in a volume of 10 ml of aqueous fluid; and thecontent of LEV in the matrix ranges from 50-80% wt based upon the totalweight of the matrix. The matrix maintains a fixed and rigidthree-dimensional structure when not placed in an aqueous fluid butdisperses in a short period of time (as defined herein) when placed in asmall volume of aqueous fluid (as defined herein).

Some embodiments of the invention include those wherein: a) the at leastone surfactant is present in an amount ranging from about 0.05 to about1%, about 0.1 to about 0.8%, and about 0.2 to about 0.5% wt based uponthe final weight of the dosage form; b) the at least one antioxidant ispresent in an amount range from about 0.005 to about 5.0%, about 0.01 toabout 1.0%, and about 0.08 to about 0.8% based upon the final weight ofthe dosage form; c) the at least one binder is present in an amountrange from about 0.5 to about 20%, about 5 to about 15%, and about 7 toabout 13% based upon the final weight of the dosage form; d) the atleast one disintegrant is present in an amount range from about 3 toabout 35%, about 10 to about 30%, and about 20 to about 26% based uponthe final weight of the dosage form; and/or e) the at least one glidantis present in an amount range from about 0.1 to about 2.0%, about 0.25to about 1.5%, and about 0.5 to about 1.0% wt, based upon the finalweight of the dosage form.

The LEV particles have an average, mean or median particle size in therange of about 50 to about 400 microns, about 50 to about 300 microns,about 50 to about 250 microns, about 60 to about 250 microns, about 60to about 100 microns, or about 75 to about 250 microns. The particlesize can be expressed as VMD. In some embodiments, the particle sizerange is defined as: a) Dv10 is about 20-60 microns, Dv50 is about 50 to200 microns, and Dv90 is about 100-500 microns; b) Dv10 is about 50-60microns, Dv50 is about 150 to 200 microns, and Dv90 is about 350-510microns; c) Dv10 is about 20-30 microns, Dv50 is about 50 to 60 microns,and Dv90 is about 100-120 microns; d) Dv10 is about 30-40 microns, Dv50is about 70-80 microns, and Dv90 is about 160-190 microns; or e) Dv10 isabout 40-50 microns, Dv50 is about 125 to 150 microns, and Dv90 is about300-350 microns. In some embodiments, the VMD ranges from about 60 toabout 240 microns, from 50-70 microns, from 80-100 microns, from 150 to175 microns, from 200 to 250 microns.

Some embodiments of the invention include those wherein the matrixcomprises about 250 to about 1000 mg, about 250 mg, about 500 mg, about750 mg, about 1000 mg of LEV.

The matrix rapidly disperses (disintegrates) in a small amount ofaqueous fluid. Some embodiments of the invention include those whereinthe matrix disperses in about 30 sec or less, about 20 sec or less,about 15 sec or less, about 10 sec or less, or about 5 sec or less whenplaced in a small amount of aqueous fluid.

Some embodiments of the invention include those wherein: a) the hardnessof the matrix ranges from about 1 to about 10 kp, about 2 to about 6 kpor about 3 to about 9 kp; b) the matrix disperses in 10 sec or less whenplaced in 15 ml of water or saliva; c) binder is introduced into thematrix by way of printing fluid used to form the matrix; d) binder isintroduced into the matrix by way of bulk powder used to form thematrix; e) the matrix comprises about 250 mg to about 1000 mg of LEV; f)the matrix comprises 15 to 50 or 25 to 50 of printed incremental layers;g) the thickness (height) of an incremental layer ranges from 0.008 to0.012 inches; and/or h) the matrix is porous and non-compressed.

The invention also provides a method of preparing a three-dimensionallyprinted orodispersible dosage form comprising LEV. The method comprises:a) providing an incremental layer of bulk powder comprising LEV,disintegrant, binder, antioxidant, optional flavorant, optionalsweetener, and optional glidant; b) according to a predeterminedsaturation level, applying a printing fluid to the layer of bulk powderto form an incremental printed layer, wherein the fluid comprises water,alcohol, binder, antioxidant, glycerin, surfactant (emulsifier),optional sweetener, optional preservative; and c) repeating a) and b) atleast two times, thereby forming the three-dimensionally printedorodispersible dosage form comprising at least three stacked incrementalprinted layers. The antioxidant can be included in the binding fluid,the powder or both.

Some embodiments of the invention include those wherein: a) the processfurther comprises forming an indicum or indicia on the surface of thedosage form in embossed (raised) or debossed (recessed) form during the3DP process; b) the process further comprises removing water and alcoholfrom the dosage form to reduce its moisture content to within a range asdescribed herein; c) the process further comprises separating the dosageform from bulk powder that has not been printed upon; d) a higherprinting fluid saturation level is used for the upper and lowerincremental layers of the dosage form than for the rest of the dosageform to provide, in the finished dosage form, increased hardness for theupper and lower incremental surfaces and reduced hardness forincremental layers there between; e) a higher printing fluid saturationlevel is used for the upper and lower incremental layers and for theperiphery of the intermediate incremental layers of the dosage form thanfor the rest of the dosage form to provide, in the finished dosage form,increased hardness for its upper and lower incremental surfaces and forthe periphery of its intermediate incremental layers and to providereduced hardness for incremental layers there between; f) the processfurther comprises heating the dosage form to remove and reduce theamount of printing fluid therein; and/or g) the process furthercomprises preparing the bulk powder by mixing the ingredients thereof toform a mixture that is then sieved.

Some embodiments of the invention include those wherein the printingfluid saturation level used to prepare the incremental printed layersranges from 40% to 120%.

A method of treating a disease or disorder that is therapeuticallyresponsive to LEV is provided. The method comprises daily administrationof one, two or three dosage forms of the invention to a subject in needthereof over a treatment period lasting days, weeks or months therebyreducing or eliminating one or more symptoms of the disease or disorder.In some embodiments, a 3DP dosage form described herein comprising adose of about 250 to about 1000 mg is administered twice daily for atreatment period. The invention also provides a method of treatingepilepsy, or other disease, disorder or condition that istherapeutically responsive to LEV, comprising: orally administering to asubject in need thereof a LEV-containing three-dimensionally printedorodispersible dosage form as described herein.

A method of preparing an orodispersible dosage form is also provided.The method comprises forming a non-compressed porous matrix as describedherein by forming incremental layers of powders and depositing printingfluid on each incremental layer to bind disintegrant, binder,surfactant, antioxidant, glidant and LEV into a rapidly orodispersiblenon-compressed porous matrix.

The invention includes all combinations of the aspects, embodiments andsub-embodiments of the invention disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The following figures form part of the present description and describeexemplary embodiments of the claimed invention. The skilled artisanwill, in light of these figures and the description herein, be able topractice the invention without undue experimentation.

FIG. 1 depicts a sectional front elevation of an orodispersible dosageform made from a three-dimensionally printed matrix comprisingsequentially-formed incremental layers of bound bulk material.

FIG. 2 depicts a sectional front elevation of an alternate embodiment ofan orodispersible dosage form made from a three-dimensionally printedmatrix.

FIGS. 3A-3E depict various different printing patterns that can be usedto apply printing fluid to incremental layers of powder.

DETAILED DESCRIPTION OF THE INVENTION

As used herein and unless otherwise specified, the term levetiracetam(LEV) refers to the drug in underivatized form((S)-2-(2-oxopyrrolidin-1-yl)butanamide;(−)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide; described in U.S. Pat.No. 4,943,639) or derivatized form. Levetiracetam is available from TEVA(Jerusalem, Israel) and Hetero Labs (Hyderabad, India), Esteve(Tarragona, Spain), Aurobindo (Hyderabad, India), Matrix Labs (Karachi,Pakistan), Srini (Hyderabad, India). LEV can be present in crystallineor amorphous form. All polymorphs of crystalline LEV and mixturesthereof can be used.

The dosage form of the invention undergoes immediate and very rapiddisintegration/dispersion of its solid matrix, and LEV and excipients inthe matrix undergo a rapid dispersion even when placed in a small volumeof aqueous fluid, such as water, saliva, juice, milk, beverage, bodyfluid, soda or a combination thereof. Dispersion (used interchangeablywith disintegration) typically, but not necessarily, overlaps with thedissolution. The matrix comprises a three-dimensional shape that isdispersed within the desired time period upon contact of the compositionwith at least a small volume of aqueous fluid.

The present invention provides a pharmaceutical composition suitable foradministration to a subject, the composition comprising LEV contained ina rapidly dispersing, non-compressed solid matrix, the matrix having afixed three-dimensional shape and comprising a bulk material and abinder, the bulk material comprising a pharmaceutically acceptablecompound in particulate form and the binder comprising apharmaceutically acceptable, substantially water-soluble substancehaving the capacity to adhere to and bind together the particles of thebulk material, to maintain the three-dimensional shape of the matrix,when not placed in an aqueous liquid, and to permit the composition toexhibit hardness and friability characteristics adequate for storage andhandling. In some embodiments, the matrix comprises LEV, binder,disintegrant, glycerin, and surfactant.

Three-dimensionally printed (3DP) dosage forms comprising the matrixwere prepared according to Example 1. The resulting 3DP dosage formswere evaluated (Example 3) for hardness, dispersion time and friabilityto determine which of the drug-containing particles provided suitable3DP orodispersible dosage forms with very rapid dispersion times,adequate hardness and minimal friability.

It has been determined that inclusion of a surfactant in the printingfluid, bulk powder and drug-containing particles aids in ensuring rapiddispersion of the 3DP dosage form when placed in a minimal amount ofwater. The surfactant serves to enhance wetting of the particles. Thesurfactant need only be present in an amount sufficient to enhancedispersion as compared to another 3DP dosage form excluding thesurfactant. If the surfactant is present in too high of an amount,however, it will negatively impact mouth feel, performance and/orphysical properties of the dosage form. The surfactant can be includedin the bulk powder and/or printing fluid. In some embodiments, theamount of surfactant present in the printing fluid ranges from about 0.1to about 4%, about 1 to about 3% or about 1.5 to about 2.5% wt. basedupon the weight to the printing fluid.

The rapidly dispersible dosage form can disperse (disintegrate) in about20 seconds or less, in about 15 seconds or less, in about 10 seconds orless, in about 5 sec or less, in about 4 sec or less, or in about 3.5sec or less when placed in a small volume of aqueous fluid, such as asaliva, gastric fluid and/or a sip of water. In some embodiments, thedispersion (disintegration) time is measured in a small volume of 20 mlor less, 15 ml or less, 10 ml or less, 5 ml or less, 3 ml or less and atleast 1 ml of an aqueous fluid. In some embodiments, the disintegrationtime is determined according to USP <701>.

The small volume of aqueous fluid can be a sip such as a volume lessthan 50 ml, less than 40 ml, less than 30 ml, less than 20 ml, less than10 ml, less than 5 ml, less than 2.5 ml, or less than 1 ml. The smallvolume can be at least 0.1 ml, at least 0.25 ml, at least 0.5 ml, atleast 0.75 ml, at least 1 ml, at least 1.5 ml or at least 2 ml. Allpossible combinations of these volumes are contemplated. Suitable rangesfor the small volume include 0.1 to 50 ml, 0.1 to 40 ml, 0.1 to 30 ml,0.1 to 20 ml, 0.1 to 10 ml, 0.2 to 10 ml, 0.3 to 10 ml, 0.5 to 10 ml, 1to 10 ml, 1 to 7.5 ml, 1 to 5 ml, 0.5 to 3 ml, or other such ranges.Preferably a sip is about 2 to about 30 ml, about 10 to about 15 ml (1tablespoon) or about 13 ml of water (fluid).

In some embodiments, the dosage form comprises not more than 10% wt.,not more than 7.5% wt., not more than 5% wt., not more than 4% wt., notmore than 3% wt., not more than 2.5% wt., not more than 2% wt. or notmore than 1.5% wt. moisture as determined by loss on drying (LOD) at120° C. In some embodiments, the dosage form comprises at least 0.1%wt., at least 0.2% wt., at least 0.5% wt., at least 0.75% wt., at least1% wt., at least 1.5% wt., at least 2% wt., at least 2.5% wt., at least3% wt., at least 4% wt., or at least 5% wt. moisture as determined byloss on drying at 120° C. In some embodiments, the dosage form comprises0.1 to 10% wt, 0.2 to 7.5% wt, 0.5 to 5% wt, 0.5 to 4% wt or 1 to 3% wtmoisture. All combinations of these various limits are within the scopeof the invention.

The dosage form is a rapidly dispersing dosage form having superioroverall hardness and friability characteristics. The hardness of thematrix can be the same (uniform) throughout the matrix, or it can vary.In some embodiments, the hardness of the exterior surfaces of the dosageform (or matrix) is greater than the hardness of an interior portion ofthe dosage form (or matrix), i.e. the exterior of the dosage form isharder than the interior. The exterior hardness can be at least1.05-fold, at least 1.1-fold, at least 1.2-fold, at least 1.3-fold, atleast 1.4-fold, at least 1.5-fold, at least 1.75-fold, at least 2-fold,at least 2.5-fold, at least 3 fold, at least 5-fold, at least 7-fold, orat least 10-fold higher than the interior hardness. In some embodiments,the upper and lower exterior surfaces have a greater hardness than theinterior portion (one or more interior layers) of the dosage form.Methods of achieving uniform hardness and varying hardness of the matrixare discussed herein. In some embodiments, the dosage form has a shelflife of at least six months or at least one year.

In some embodiments, the overall hardness (as determined by a tabletbreaking force assay according to USP <127>) of the matrix ranges from 1kp to about 20 kp, from about 1 kp to about 10 kp, from about 1 kp toabout 7 kp, from about 3 to about 9 kp, about 1 to about 3 kp, about 4.5to about 6 kp, about 2.5 to about 6.5 kp, about 3 to about 6 kp, or fromabout 1 kp to about 5 kp. In some embodiments, the overall hardness isat least 1 kp, at least 2 kp, or at least 3 kp. In some embodiments, theoverall hardness is no more than 10 kp, no more than 8 kp or no morethan 6 kp.

The term friability refers to the tendency of the matrix to losematerial from its outer edges and surfaces upon mechanical insult.Friability is reduced by increasing the hardness. In some embodiments,the dosage form possesses a friability of less than about 25%,preferably less than about 10% as determined according to USP <1216> andas further described below.

In some embodiments, the porosity of the matrix ranges from about 10% toabout 90% or from about 30% to about 70% of the dosage form volume.

In some embodiments, the bulk density of the matrix (as determined bymeasurement and/or calculation) ranges from 150 (mg/mL) to about 1300(mg/mL) or from about 400 (mg/mL) to about 1000 (mg/mL).

Dissolution time of the LEV is slower than dispersion time of the matrixof the dosage form when placed in an aqueous fluid. Some embodiments ofthe invention include those wherein not less than 75% wt. (or wherein atleast 75% wt.) of LEV present in the dosage form dissolves in 20 min orless, 10 min or less, 5 min or less, 4 min or less, 3 min or less, 2 minor less or 1 min or less when placed in an aqueous environment. Otherembodiments of the invention include those wherein not less than 95% wt.(or wherein at least 95% wt.) of LEV present in the dosage formdissolves in 20 min or less, 10 min or less, 5 min or less, 4 min orless, 3 min or less, 2 min or less or 1 min or less when placed in anaqueous environment or in water. In some embodiments, the dissolutiontimes above may be achieved in aqueous environments characterized by apH of 1.2 or 4.5 or 6.8, and tested within a USP paddle apparatus at 50RPM or 75 RPM or 100 RPM and a volume of 900 mL or 950 mL or 1000 mL.

The rapidly dispersible dosage form of the invention is made by athree-dimensional printing (3DP) process. Suitable equipment assembliesfor three-dimensional printing of articles are commercially available orare already in use: Massachusetts Institute of TechnologyThree-Dimensional Printing Laboratory (Cambridge, Mass.), ZCorporation's 3DP and HD3DP™ systems (Burlington, Mass.), The Ex OneCompany, L.L.C. (Irwin, Pa.), Soligen (Northridge, Calif.), SpecificSurface Corporation (Franklin, Mass.), TDK Corporation (Chiba-ken,Japan), Therics L.L.C. (Akron, Ohio, now a part of IntegraLifesciences), Phoenix Analysis & Design Technologies (Tempe, Ariz.),Stratasys, Inc.'s Dimension™ system (Eden Prairie, Minn.), ObjetGeometries (Billerica, Mass. or Rehovot, Israel), Xpress3D (Minneapolis,Minn.), and 3D Systems' Invision™ system (Valencia, Calif.). Othersuitable 3DP systems are disclosed in U.S. No. 20080281019, No.20080277823, No. 20080275181, No. 20080269940, No. 20080269939, No.20080259434, No. 20080241404, No. 20080231645, No. 20080229961, No.20080211132, No. 20080192074, No. 20080180509, No. 20080138515, No.20080124464, No. 20080121172, No. 20080121130, No. 20080118655, No.20080110395, No. 20080105144, No. 20080068416, No. 20080062214, No.20080042321, No. 20070289705, No. 20070259010, No. 20070252871, No.20070195150, No. 20070188549, No. 20070187508, No. 20070182799, No.20070182782, No. 20060268057, No. 20060268044, No. 20060230970, No.20060141145, No. 20060127153, No. 20060111807, No. 20060110443, No.20060099287, No. 20060077241, No. 20060035034, No. 20060030964, No.20050247216, No. 20050204939, No. 20050179721, No. 20050104241, No.20050069784, No. 20050061241, No. 20050059757, No. 20040265413, No.20040262797, No. 20040252174, No. 20040243133, No. 20040225398, No.20040183796, No. 20040145781, No. 20040145628, No. 20040143359, No.20040141043, No. 20040141030, No. 20040141025, No. 20040141024, No.20040118309, No. 20040112523, No. 20040012112, No. 20040005360, No.20040005182, No. 20040004653, No. 20040004303, No. 20040003741, No.20040003738, No. 20030198677, No. 20030143268, No. 20020125592, No.20020114652, No. 20020079601, No. 20020064745, No. 20020033548, No.20020015728, No. 20010028471, and No. 20010017085; U.S. Pat. No.5,490,962, No. 5,204,055, No. 5,121,329, No. 5,127,037, No. 5,252,264,No. 5,340,656, No. 5,387,380, No. 5,490,882, No. 5,518,680, No.5,717,599, No. 5,851,465, No. 5,869,170, No. 5,879,489, No. 5,934,343,No. 5,940,674, No. 6,007,318, No. 6,146,567, No. 6,165,406, No.6,193,923, No. 6,200,508, No. 6,213,168, No. 6,336,480, No. 6,363,606,No. 6,375,874, No. 6,508,971, No. 6,530,958, No. 6,547,994, No.6,596,224, No. 6,772,026, No. 6,850,334, No. 6,905,645, No. 6,945,638,No. 6,989,115, No. 7,220,380, No. 7,291,002 No. 7,365,129, No.7,435,368, No. 7,455,804, No. 7,828,022, No. 8,017,055; PCTInternational Publications No. WO 00/26026, No. WO 98/043762, No. WO95/034468, No. WO 95/011007; and European Patent No. 1,631,440, whichemploys a cylindrical (radial or polar) coordinate-based system due toits construction. The entire disclosure of each of these references ishereby incorporated herein.

The 3DP process described herein requires a powder layering system thatforms a layer of powder and printing system that applies a printingfluid to the layer of powder according to a predetermined pattern,thereby forming an incremental printed layer. The printing fluid servesto form bound particles of powder, i.e. particles that are adhered toone another by one or more pharmaceutical excipients and/or one or moreactive ingredients. Incremental printed layers are formed one on top ofanother to vertically build the dosage form of the invention, therebyforming a dosage form comprising plural incremental printed layers. Theprocess of spreading powder and depositing droplets is repeated untilthe desired number of layers for the dosage form is complete. The layersadhere to one another due to bleeding of printing fluid from one layerto an adjacent other layer such that one or more excipients and/or oneor more active ingredients adhere to both adjacent layers. Followingcompletion of the initial three-dimensional structure, residual printingfluid is removed from or reduced in the dosage form by drying. Theevaporation of solvent during the drying process leaves a matrix havinga three-dimensional architecture comprising the particles of bulkmaterial bound by solidified binder and/or other components includingone or more active ingredients and/or any optional pharmaceuticallyacceptable excipients.

The three-dimensional printing process is normally conducted at ambienttemperatures. The process can utilize a variety of printing fluids,including biologically compatible organic and aqueous solvents. Theprocess is additive, whereby microscopic features are incorporated layerby layer, allowing a wide range of possible architectures to beconstructed precisely on a sub-millimeter scale. Using three-dimensionalprinting to control simultaneously both the microscopic features and themacroscopic shape, the unique drug delivery systems of the presentinvention are obtained.

A particularly suitable printing assembly for three-dimensional printingof the instant dosage form is described in U.S. application No.61/696,839, filed Sep. 5, 2012, the disclosure of which is herebyincorporated by reference in its entirety. The assembly includes buildmodules each having an incrementally height adjustable platform disposedwithin a cavity of the build modules, a powder layering system, aprinting system, a printing fluid removal system and a dosage formhandling system.

In general, at least two components are used in the three-dimensionalprinting process used to prepare the matrix of the rapidly dispersingdosage forms. The first component is the bulk powder material to beincluded in the incremental powder layers. The second component is theprinting fluid (in some cases the fluid may also contain a binder) thatis dispensed by a printhead onto the powder layer. In some embodiments,the bulk powder material is comprised of one or more pharmaceuticallyacceptable excipients, LEV, disintegrant, binder and surfactant.

At least one component of the matrix must serve as a “binding agent”that binds particles of bulk powder together in the completedthree-dimensional matrix. The binding agent produces adhesion betweenparticles of the bulk powder. It is this adhesion that enables thedosage form to maintain a fixed shaped (geometry) and maintain itscharacteristics of hardness and friability adequate to permit handlingand storage. The strength and extent of the particle binding depends onthe proportion of the binding agent either in the powder layer ordissolved in the solvent, and is a function of the amount of fluiddeposited. The term adhesion means the bonding or binding of particlesof the bulk material to each other or to particles of another materialpresent, such as particles of binder or active ingredient. There arevarious ways in which a binding agent can be included in the matrix. Theinvention contemplates a combination of one or of two or more of thesedifferent ways.

In some embodiments of the method of preparation of the matrix, bindingagent is present in the bulk powder, the printing fluid, or both. Abinding agent in the printing fluid can be the same as or different thana binding agent in the bulk powder.

The binding agent can be a binder, LEV, another pharmaceuticalexcipient, or a combination thereof. In some embodiments, the bindingagent is: a) at least LEV; b) at least binder; or c) binder and LEV. Insome embodiments, two or more binding agents are present in the matrix.Including a “binder” as the binding agent in the printing fluid willresult in a different internal microstructure of the wafers,particularly the pore size, than the internal microstructure of anotherwise same wafer excluding binder in the binding solution. Uponprinting, as the solvent evaporates, binder remains as a solid residue,which occupies void space in between powder particles, e.g. particles ofdisintegrant or drug. The resulting structure will have higher densitycompared to tablets fabricated without binder in the printing fluid.

The invention provides a process for the preparation of a rapidlydispersing solid dosage form comprising a three-dimensionally printedsolid porous matrix comprising a bulk powder, binder and LEV, theprocess comprising: (a) providing a powdered mixture of one or moredisintegrants, one or more binders, one or more glidants and LEV,together with any optional pharmaceutically acceptable excipients; (b)forming an incremental layer of the powdered mixture; (c) applying tothe incremental layer droplets of printing fluid according to apredetermined pattern to form a printed incremental layer; (d) repeating(b) and (c) a predetermined number of times, thereby providing athree-dimensionally printed moist matrix; and (e) removing printingfluid from the moist matrix, thereby providing three-dimensionallyprinted solid porous matrix having a composition, moisture content,porosity, overall bulk density, hardness, matrix dispersion time, invitro drug dissolution time, in vitro dispersion behavior, in vivopharmacokinetic behavior, structure, incremental layer thickness, drugparticle size, disintegrant particle size, drug content, and/orfriability within the ranges specified herein.

The dosage form of the present invention may be further shaped asdesired to facilitate placement thereof in the buccal cavity of asubject. One such embodiment may be a wafer-like shape.

FIG. 1 depicts a sectional front elevation of an orodispersible dosageform (1) made from a three-dimensionally printed matrix comprisingsequentially-formed incremental layers of bound bulk material (2-3). Theexterior surfaces (3) envelope a middle portion (2). The exteriorsurfaces have a greater hardness than the interior portion. This dosageform is made by three-dimensionally printed plural incremental layers.The bottom incremental layer, which defines the lower surface, and theupper incremental layer, which defines the upper surface, and thecircumferential surfaces (left and right of the middle portion) areharder than the interior portion. The increased hardness is achieved byusing a higher saturation level, higher content of binder or asotherwise described herein. The increased hardness at the periphery ofthe incremental layers of the middle portion is achieved by increasingthe saturation level and/or content of binder at the periphery, but notthe center (non-peripheral portion) of the respective incrementallayers.

FIG. 2 depicts a sectional front elevation of an alternate embodiment ofan orodispersible dosage form (5) made from a three-dimensionallyprinted matrix. The bottom incremental layer, which defines the lowersurface (8), and the upper incremental layer, which defines the uppersurface (7) are harder than the interior portion (6) comprising pluralincremental layers. The dosage forms (1) and (5) differ primarily in theprocess used to print the middle incremental layers, the layers of (6)not having a periphery with increased hardness.

FIGS. 3A-3E depict the top plan view of three different print patternsthat can be used to prepare the printed incremental layers of a 3DPorodispersible matrix of the invention. Even though each print patternis depicted as being circular, substantially any geometry can be used,e.g. circle, oval, square, rectangle, oblong circle, etc. FIG. 3Adepicts a first solid print pattern wherein substantially the same full,heavy or higher saturation level is used throughout the entire printarea. FIG. 3B depicts a second solid print pattern wherein substantiallythe same medium, low, light or lower saturation level is used throughoutthe entire print area. This second solid pattern is referred to as agrayscale pattern since it has a reduced saturation level. Where solidprinting is initially defined as a saturation ranging from 90 to 120%,grayscale printing is defined as saturation of less than 90%, orsaturation of about 20 to <90%, or about 20 to about 85%, or about 20 toabout 80%, about 20%, about 35%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, or any fractional or integer increments in theseranges.

FIG. 3C depicts an annular (hollow) print pattern wherein printing fluidis applied to the periphery of the print area but not toward the centerof the print area. FIG. 3D depicts a combination annular and grayscaleprint pattern wherein printing fluid is applied to the periphery of theprint area at a higher saturation level and toward the center of theprint area at a grayscale (reduced) saturation level. The radialthickness (as measured from the center of the circle) of the peripheralring in the print patterns in FIGS. 3D and 3D can be varied as needed.The ring thickness can range from about 0.05 to 10 mm depending upon thediameter of the dosage form. It can range from about 0.1 to about 7 mm,about 0.5 to about 7 mm, about 1 to about 5 mm, or about 1.5 to about3.5 mm.

FIG. 3E depicts an indicum print pattern wherein substantially the samesaturation level is used throughout the entire print area except in theindicum region(s) wherein no printing fluid is applied thereby forming adebossed indicum in the surface of the final dosage form.

In some embodiments, the dosage form comprises (consists essentially ofor consists of) the following types of printed incremental layers: a)plural layers of first solid print pattern, and plural layers ofcombination annular and grayscale print pattern; b) plural layers offirst solid print pattern, plural layers of annular print pattern, andplural layers of combination annular and grayscale print pattern; c)plural layers of first solid print pattern, plural layers of annularprint pattern, plural layers of combination annular and grayscale printpattern, and plural layers of indicum print pattern; d) plural layers offirst solid print pattern, plural layers of annular print pattern,plural layers of combination annular and grayscale print pattern, plurallayers of first solid print pattern, and plural layers of indicum printpattern; e) plural layers of first solid print pattern, plural layers ofgrayscale print pattern, and plural layers of first solid print pattern;f) plural layers of grayscale print pattern; g) plural layers ofcombination annular and grayscale print pattern; h) plural layers offirst solid print pattern; i) plural layers of first solid print patternand plural layers of annular print pattern; or j) plural layers of firstsolid print pattern, plural layers of combination annular and grayscaleprint pattern, and plural layers of indicum print pattern.

In some embodiments, the dosage form comprises (consists essentially ofor consists of) the following types of incremental layers grouped intorespective sections of the dosage form: a) a first end comprising plurallayers of first solid print pattern; a middle portion comprising plurallayers of annular print pattern and plural layers of combination annularand grayscale print pattern; and a second end comprising plural layersof indicum print pattern; b) a first end comprising plural layers offirst solid print pattern; a middle portion comprising plural layers ofcombination annular and grayscale print pattern; and a second endcomprising plural layers of first solid print pattern and/or plurallayers of indicum print pattern; c) a first end comprising plural layersof first solid print pattern; a middle portion comprising plural layersof annular print pattern, plural layers of combination annular andgrayscale print pattern; and a second end comprising plural layers offirst solid print pattern and/or plural layers of indicum print pattern;or d) a first end comprising plural layers of first solid print pattern;a middle portion comprising alternating groups of layers, wherein onegroup comprises plural layers of annular print pattern, and anothergroup comprises plural layers of combination annular and grayscale printpattern; and a second end comprising plural layers of first solid printpattern and/or plural layers of indicum print pattern.

The physical properties of the dosage form can be controlled by varyingincremental powder layer thickness, powder composition, printing fluidcomposition, printing fluid saturation level (print density) on a layer,and identity and amount of the excipients included within the dosageform, e.g. identity and amount of disintegrant, binder, sweetener,surfactant. These variables exhibit different levels of effect upondosage form hardness, bulk density, disintegration time, dissolutiontime, bioavailability, moisture content, mouthfeel and friability. Itwas determined that the result effective variables include, at least,the amount of drug, amount of disintegrant, amount of binder, identityof some components, and composition of the drug-containing particles.

Three-dimensional printing can have spatial descriptors in each of threedifferent, typically orthogonal directions. In three-dimensionalprinting, fluid may be deposited in drops or in fluid units resemblingdrops. Drops may be deposited in a succession that forms a linecorresponding to the motion of the printhead. The spacing between thosedrops is the drop-to-drop spacing. After completion of one line, anotherline may be deposited adjacent to the earlier-deposited line andseparated from the earlier-deposited line by a distance that is aline-to-line spacing. After completion of printing on a layer of powder,another powder layer may be deposited, with each powder layer having alayer thickness. The powder layer thickness is the third descriptor.

In some instances, the spacing of droplets may be described in terms ofthe resolution of the printing system, often expressed as dots per inch(dpi), which is the reciprocal of droplet spacing. For example,resolutions of 300 and 600 dpi correspond to droplet spacing's of about84.7 microns and about 42.3 microns, respectively. The drop-to-dropspacing (within a line), or the line spacing (spacing of droplets fromone line to the next), or any other spacing of droplets may be describedin terms of resolution expressed in dpi. In some instances,layer-by-layer instructions for making the dosage forms may consist of aseries of pixelated images characterized by a resolution indots-per-inch in each of two orthogonal linear directions. In someinstances, these pixelated images are 1-bit monochrome images,alternately referred to as binary or bi-level images in which each pixelcontains one bit of information (0 or 1) that may be represented aseither black or white onscreen.

In some instances, the relative amount of binding in localized regionsof the dosage form is achieved by “grayscaling” (i.e., use of agrayscale print pattern) in the dosage form design. In the case of 1-bitmonochrome images used for machine instructions, grayscaling is achievedby changing the number of “black” pixels relative to “white” pixels in achosen region of a dosage form, or in a chosen layer of a dosage form,or throughout a dosage form. Any other regions that may be “solid” byusing all black pixels. In some embodiments, the dosage form designincludes a “solid” exterior and a “grayscaled” interior. In someembodiments, grayscaling may be achieved with equally spaced blackpixels amongst white pixels to reach an overall ratio of black to whitepixels in the grayscaled region. In other embodiments, grayscaling maybe achieved with randomly placed black pixels amongst white pixels toachieve an overall ratio of black to white pixels in the grayscaledregion. In still other embodiments, grayscaling may be achieved with achosen pattern (e.g., parallel lines, hashed pattern, dot pattern) ofblack pixels amongst white pixels to achieve an overall ratio of blackto white pixels in the grayscaled region.

In three-dimensional printing, a voxel or unit volume may be defined byone drop-to-drop spacing in the fast axis direction of motion, by oneline-to-line spacing in the slow axis direction of motion, and by onelayer thickness in the vertical direction. Some of this unit volume isoccupied by powder particles, and the remainder of the unit volume isempty space that collectively has a volume that is the void volume.

The saturation level (print density) describes how much of the voidspace in this unit volume is occupied by liquid which is dispensed in adrop or fluid unit which is dedicated to that particular voxel. Thesaturation level is the ratio of the dispensed fluid volume to thevolume of empty space in the voxel. In general, in three-dimensionalprinting, saturation levels may be chosen to be slightly less than, orsomewhere approximately equal to, 1.0, also expressed as 100%.Excessively low saturation levels tend to result in poor structuralintegrity. Excessively high saturations levels tend to result inexcessive bleeding of liquid beyond where the liquid was deposited. Inthe present dosage form, the saturation level during the step ofapplying printing fluid to a powder layer ranges from about 10% to about110%, about 15% to about 80%, about 20% to about 50% or about 15% toabout 35% in aggregate across the dosage form, or otherwise in selectedregions of the dosage form.

Suitable printing devices include those having a continuous jetprinthead or those having a drop-on-demand printhead. A continuous jetprinthead provides a continuous jet (spray) of droplets while depositingprinting fluid onto a powder layer. A drop-on-demand printhead onlydeposits droplets of printing fluid onto the powder layer if it receivesan instruction (demand, operational command) to do so. A printhead scans(applies fluid to) the surface of powder layer from left to right at apredetermined rate, e.g. a scan rate, to form a line of droplets. A highscan rate will result in a lower saturation level, and a low scan ratewith result in a higher saturation level when comparing printing fluiddeposition at a constant volume per unit time. When considering thesituation where binder is present in the binding solution, an increasein the print speed from 1.0 m/s to 2.0 m/s reduces the total volume ofbinder solution deposited in the tablets by half. As the print speedincreases, the bulk density (theoretical, calculated from the weight anddimensions of the tablet) decreases. A simultaneous decrease in thedimensions and weight of the tablets is also seen. This decrease isattributed to the fact that a decrease in the total volume of binderdroplets deposited onto the powder results in a decrease in the extentof binder solution spreading in the powder. Increasing the print speedalso decreases the flash time and the hardness and increases thefriability of the tablets. This result is obtained because theproportion of binder decreases in the tablets as the print speedincreases. An increase in the print speed also increases the void volumeinside the tablets, as illustrated by an increase in the percent volumeof the tablets penetrated by mercury at 30 psi (% intrusion).

When using a continuous jet printhead, the printhead scans at a rate ofabout 0.5 to 3.0 m/sec, and most preferably at about 1.75 m/sec. Whenusing a drop-on-demand jet printhead, the printhead scans at a rate of0.1 to 1 m/sec, most preferably at about 0.15 to about 0.5 m/sec.

The volume of individual droplets can be varied as desired, for example,by selection of a different three-dimensional printing machine, ordifferent printhead components on the same machine, or differentparameters on the same printhead and same machine. Increasing the volumeof the droplet increases the saturation level and decreasing the volumeof a droplet decreases the saturation level when comparing printingfluid deposition at a constant scan rate. When using a continuous jetprinthead, the size of the fluid droplets delivered by the printheadpreferably ranges from about 15 μm to about 150 μm in diameter. Whenusing a drop-on-demand printhead, the size of the fluid dropletsdelivered by the printhead preferably ranges from about 50 μm to about500 μm in diameter.

The flow rate of the fluid delivered by the printhead can be varied asdesired. Increasing the flow rate will increases the saturation leveland decreasing the flow rate decreases the saturation level whencomparing printing fluid deposition at a constant scan rate. Asdiscussed herein, the printhead deposits droplets of printing fluid toform parallel lines thereof in the powder layer. When using a continuousjet printhead, the line spacing ranges from about 20 to about 1000 μm,about 50 to about 500 μm, or and preferably about 100 to 200 μm. Whenusing a drop-on-demand jet printhead, the line spacing ranges from about20 to about 300 μm, about 40 to about 100 μm, or about 55 to 75 μm.

The powder layering system and the height adjustable platform cooperateto form thin incremental layers of powder in the build modules. Thetotal thickness (height) of the dosage form will be a function of thenumber and thickness of the incremental layers. The number of printedincremental layers typically ranges from 5 to 50. In some embodiments,the number of printed incremental layers ranges from 10 to 50, to 45 or20 to 40. A matrix will typically comprise (consist essentially of orconsist of) 20 to 50, 20 to 40, 25 to 40, 30 to 40 or 30 to 35 printedincremental layers. The “end” section of a dosage form will typicallycomprise 1 to 10, 1 to 7, 2 to 7, 2 to 5, or 4 to 6 printed incrementallayers. An end section with an indicum will typically comprise 2 to 10,2 to 7, 2 to 5, or 4 to 7 printed incremental layers. The balance of theprinted incremental layers will comprise the middle portion, withrespect to the vertical height, of the dosage form. The middle portionwill typically comprise 5 to 40, 10 to 30, 10 to 20, or 20 to 30 printedincremental layers.

Wafers (matrices, dosage forms) produced by the 3DP process describedherein vary in size according to the content of LEV and of excipientsrequired to provide dosage forms exhibiting the desired properties. Ifthe matrix comprises a higher dose of LEV, then a larger wafer isrequired as compared to another 3DP dosage form having the samepercentage but lower dose of LEV. If a higher percentage of LEV is used,the dosage form weight can be decreased correspondingly and vice versa.Wafer-shaped dosage forms of the invention ranged in diameter from about13-14 mm (lowest dose) to about 20-25 mm (highest dose) and in heightfrom about 5-6 mm (lowest dose) to about 8-10 mm (highest dose).

The incremental layers are of a predetermined height (verticalthickness), which typically varies from 0.005 to 0.015 inches, 0.008 to0.012 inches, 0.009 to 0.011 inches, about 0.01 inches, 100-300 μm,100-500 μm, about 200 μm, or about 250 μm. As thicker incremental layersare used, an increasing amount of printing fluid must be deposited onthat layer to ensure adequate binding both within the plane of the layerand layer-to-layer. Conversely, for a thinner incremental layer a lesseramount of printing fluid must be deposited to obtain the same extent ofbinding. For a given amount of printing fluid deposited per layer, usinga larger layer thickness will reduce (worsen) dosage form handleabilityand reduce (improve) dispersion time. If too thick of a layer is usedfor a given amount of fluid, laminar defects may form that cause thedosage form to easily fracture along the plane of the layers(delamination), or the dosage form itself may not have adequate strengthto handle at all. In some embodiments, the thickness of the incrementallayers ranges from 100-400 microns, 150-300 microns, or 200-250 microns.In one preferred embodiment, the layer thickness is 200 microns. Inanother preferred embodiment, the layer thickness is 250 microns.

The stability of LEV to oxidative degradation when included in a 3DPdosage form of the invention was determined by exposing finished dosageforms to heat. The formation of degradants was observed and monitored byHPLC/MS as detailed below. It was determined that LEV undergoesoxidative degradation to form oxo-levetiracetam whenever an antioxidantis absent and the formulation contains an oxidative excipient, e.g.povidone containing peroxide impurity or silica containing peroxideimpurity. Povidone and silica, however, are important functionalingredients. Accordingly, the invention provides a stable rapidlydispersible dosage form comprising LEV, oxidative excipient,antioxidant, binder and disintegrant, wherein the matrix comprises 0.1%by wt or less of an oxidative degradant of LEV after storage for sixmonths at 21° C. and 75% RH.

The present inventors determined that some of the excipients commonlyused in 3DP dosage forms can contain oxidizing compound (oxidants),which can result from the process of manufacture or the inherentinstability of the excipient(s). Some of the oxidants are believed to beperoxides. It was determined that the level of oxidant in povidoneincreases during storage after exposure of the excipient to anoxygen-containing atmosphere. Regardless of the source of oxidant, it issurprising that levetiracetam is so sensitive to oxidation when includedin a 3DP dosage form but not when included in other dosage forms, asnote in the art cited above.

Stability studies were conducted according to Example 6. The presentinventors have succeeded in identifying and selecting a group ofpreferred antioxidants that stabilize levetiracetam against oxidationthat occurs upon storage at elevated temperature and/or upon exposure toelevated temperature during the drying step of the 3DP process used toprepare the dosage form of the invention. Suitable antioxidants includesodium sulfite, sodium bisulfite, Vitamin E, methionine, BHA and BHT.Preferred antioxidants include sodium bisulfite, sodium sulfite, BHA andBHT.

One or more pharmaceutically acceptable excipients can be included inbulk powder material and/or the printing fluid. Each excipient may beindependently selected upon each occurrence from a water soluble,aqueous fluid soluble, partially water soluble, partially aqueous fluidsoluble, water insoluble or aqueous fluid insoluble excipient as neededto provide the required particle-to-particle binding in a printedmatrix.

Most pharmaceutically acceptable excipients, both small molecules andpolymers, can be employed, which allow a pharmaceutically activeingredient to be loosely encased in a porous structure (a matrix ofbound particles) that is subject to rapid dispersion in the presence ofan appropriate aqueous fluid, e.g., saliva. Some of these excipients,suitable for use in the three-dimensional printing process of theinvention, are listed in the Handbook of Pharmaceutical Excipients (Eds.A. Wade and P. J. Weller, Second edition, American PharmaceuticalAssociation, The Pharmaceutical Press, London, 1994).

Suitable types of excipients include binder, disintegrant, dispersant,sweetener, glidant, flavorant, surfactant, humectant, preservative,antioxidant and diluent. Although conventional pharmaceutical excipientsmay be used, they may not always function in precisely the same manneras with traditional pharmaceutical processing.

One or more binders can be included in the printed matrix. The bindermay be included in either the powder material or in the printing fluiddispensed through the printhead. The binder is independently selectedupon each occurrence. Adhesion of the particles to and/or by the binderoccurs either when the binder is contacted by the printing fluid fromthe printhead or when it is present (i.e., soluble) in the printingfluid. The binder is preferably water soluble, aqueous fluid soluble,partially water soluble or partially aqueous fluid soluble. In someembodiments, the printing fluid comprises 1-20% wt, 5-15% wt or 8-12% wtof binder. In some embodiments, the bulk powder comprises >0 to 10% wt,5 to 15% wt, 0 to 15% wt, 8-14% wt or 9-11% wt of binder. In someembodiments, the printed matrix comprises 1-20% wt, 5-14% wt or 8-12% wtof binder. In some embodiments, binder is absent from the printing fluidor absent from the bulk material.

Suitable binders include water-soluble synthetic polymer,polyvinlypyrrolidone (povidone), sorbitol, mannitiol, xylitol, lactitol,erythritol, pregelatinized starch, modified starch,hydroxypropylmethylcellulose and others. The preferred binder ispolyvinylpyrrolidone, e.g. PVP K30, modified starch (e.g., starch sodiumoctenylsuccinate), mannitol or a combination thereof. PVP with a K valuedifferent from 30 may be used, including without limitation PVP K25 andPVP K90.

The following materials are considered binders, even though they exhibitlow strength binding: spray dried lactose, fructose, sucrose, dextrose,sorbitol, mannitol, or xylitol.

One or more disintegrants can be included in the printed matrix. Thedisintegrant can be present in the bulk powder. The disintegrant isindependently selected upon each occurrence. In some embodiments, thebulk powder comprises 5 to 30% wt, 10 to 25% wt, 15 to 25% wt, 18 to 24%wt, 18 to 23.7% wt, 1-30% wt, 10-25% wt, 20-25% wt of disintegrant.

Suitable disintegrants include microcrystalline cellulose (MCC),crospovidone (cross-linked polyvinylpyrrolidone), croscarmellose, sodiumstarch glycolate or a combination thereof. The preferred disintegrant ismicrocrystalline cellulose. Suitable grades of AVICEL® are summarized inthe table below. The dosage form can comprise one or a combination ofthe specified grades. All such embodiments containing single grades or acombination of grades are contemplated.

Nominal Particle LooseBulk Product Grades Size, μm Moisture, % Density,g/cc Avicel DG 45 NMT 5.0 0.25-0.40 Avicel PH-101 50 3.0 to 5.00.26-0.31 Avicel PH-102 100 3.0 to 5.0 0.28-0.33 Avicel HFE*-102 100 NMT5.0 0.28-0.33 Avicel PH-102 SCG** 150 3.0 to 5.0 0.28-0.34 Avicel PH-10520 NMT 5.0 0.20-0.30 Avicel PH-102 SCG 150 3.0 to 5.0 0.28-0.34 AvicelPH-200 180 2.0 to 5.0 0.29-0.36 Avicel PH-301 50 3.0 to 5.0 0.34-0.45Avicel PH-302 100 3.0 to 5.0 0.35-0.46 Avicel PH-103 50 NMT 3 0.26-0.31Avicel PH-113 50 NMT 2 0.27-0.34 Avicel PH-112 100 NMT 1.5 0.28-0.34Avicel PH-200 LM 180 NMT 1.5 0.30-0.38 Avicel CE-15 75 NMT 8 N/A NMTmeans “not more than”.

The binder and disintegrant are key ingredients for controlling thehardness, friability and dispersion time of the matrix. The greater theamount of binder, the higher the hardness, the lower the friability andthe slower the dispersion time. On the other hand, increasing the amountof disintegrant provides lower hardness, increased friability and afaster dispersion time. Accordingly, the matrix of the inventioncomprises a balanced amount of binder and disintegrant.

One or more sweeteners can be included in the printed matrix. Thesweetener can be present in the bulk powder and/or in the printing fluidapplied to the bulk powder. Better taste-masking is observed when atleast one sweetener is present in at least the printing fluid. Thesweetener is independently selected upon each occurrence. The printingfluid and the bulk powder can have at least one sweetener in common,e.g. the printing fluid and bulk powder each comprise the same sweetenerand the bulk powder comprises an additional sweetener. In someembodiments, the bulk powder comprises >0 to 5% wt, or >0 to 2% wt,or >0 to 1.5% wt of sweetener. In some embodiments, the printing fluidcomprises >0 to 5%, or 0.5 to 4%, or 1 to 3% wt sweetener.

Suitable sweeteners are selected from the group consisting ofglycyrrhizinic acid derivative, e.g. magnasweet (monoammoniumglycyrrhizinate), sucralose, aspartame, acesulfame potassium, neotame,and a combination thereof. The preferred sweetener in the printing fluidis sucralose. The sweetener is present in at least the printing fluidand can also be present in the bulk powder.

One or more flavorants can be included in the matrix. The flavorant canbe present in the bulk powder and/or the printing fluid. The flavorantis independently selected upon each occurrence. The flavorant ispreferably water soluble, aqueous fluid soluble, partially water solubleor partially aqueous fluid soluble. In some embodiments, the printingfluid comprises 0.01-5% wt, 0.1-1% wt or 0.2-0.5% wt of flavorant. Insome embodiments, the flavorant may be provided on a powdered carrier.Suitable carriers may be chosen from starches, celluloses, and otherexcipients on which the flavorant could be absorbed, adsorbed,encapsulated, or otherwise loaded. In some embodiments, the bulk powdercomprises 0.1 to 10% wt, or 1 to 9% wt, 2 to 8% wt of flavorant-loadedcarrier. In some embodiments, the printed matrix comprises 0.1-10% wt,or 1-9% wt or 2-8% wt of flavorant-loaded carrier. In some embodiments,the flavorant is absent from the printing fluid or absent from the bulkmaterial.

Suitable flavorants include spearmint, peppermint, mint, vanilla,orange, lemon, citrus, lime, grape, cherry, strawberry, chocolate,coffee or a combination thereof.

One or more surfactants can be included in the printing fluid and/orbulk powder. The surfactant is independently selected upon eachoccurrence. In some embodiments, the printing fluid comprises 0.1 to 4%wt, 1 to 3% wt or 1.5 to 2.5% wt of surfactant.

Suitable surfactants include polysorbate (PEG-ylated sorbitan (aderivative of sorbitol) esterified with fatty acid), poloxamer or acombination thereof. Suitable polysorbates include polysorbate 20(Polyoxyethylene (20) sorbitan monolaurate), polysorbate 40(Polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60(Polyoxyethylene (20) sorbitan monostearate), polysorbate 80(Polyoxyethylene (20) sorbitan monooleate), sodium lauryl sulfate,poloxamer (comprising a central (poly(propylene oxide)) flanked by twochains of (poly(ethylene oxide), e.g. LUTROL), low molecular weightpolyethylene glycol (e.g. PEG 400). Suitable poloxamers may includepoloxamers 124, 188, 237, 338, or 407.

Even though the dosage form can be preservative-free, one or morepreservatives may optionally be included in the printing fluid or powderblend. Suitable preservatives include antifungal or antimicrobialpreservatives such as methylparaben and proprylparaben. In someembodiments, the printing fluid comprises 0.001 to 0.2% preservative.

One or more glidants can be included in the bulk powder. In someembodiments, the bulk powder comprises 0.1-2.0%, 0.25-1.5%, or 0.5-1.0%wt of glidant. Suitable glidants include fumed silica (colloidal silicondioxide).

The matrix may also comprise glycerin (glycerol) introduced thereineither by way of the bulk powder or the printing fluid. Glycerin canexhibit characteristics of a humectant, sweetener, preservative,lubricant, saponifier or solvent. The present inventors have discoveredthat glycerin unexpectedly behaves contrary to other excipients whenincluded in a three-dimensionally printed dosage form. As noted above,increasing the amount of other excipients disclosed generally results inincreased hardness with concomitantly increased disintegration time;however, increasing the amount of glycerin results in increased hardnessbut unexpectedly reduced disintegration time. The ability of glycerin tobehave in this manner is particularly advantageous and has not beenobserved with any other material incorporated into a three-dimensionallyprinted orodispersible dosage form. Therefore, it is unexpected that onecould achieve preparation of an orodispersible matrix that disperses in10 sec or less or 5 sec or less in a small volume of water.

In some embodiments, glycerin is included in the printing fluid.Accordingly, the invention provides a printing fluid for use inthree-dimensional printing wherein the printing fluid comprisesglycerin, water, and at least one organic solvent. The invention alsoprovides a three-dimensional printing method comprising: a) depositing aprinting fluid comprising glycerin, water and at least one organicsolvent onto at least one layer of powder; and b) reducing the contentof water and solvent in the at least one layer, thereby forming athree-dimensionally printed porous matrix. The invention also provides athree-dimensional printing system comprising: a) a layer-forming systemthat forms layers of powder; and b) a printing fluid deposition systemthat deposits printing fluid onto the layers of powder, wherein theprinting fluid comprises glycerin, water and at least one organicsolvent.

In some embodiments, the printing fluid comprises 1-10% wt, or 2-8% wtor 3-5% wt of glycerin. In some embodiments, the matrix comprises0.05-5% wt, 0.25-2.0% wt, 0.5-1.5% wt or 0.5-1.0% wt of glycerin.

In some embodiments, the process of the invention employs a printingfluid comprising at least one or combination of pharmaceuticallyacceptable solvent for at least one material in the bulk powder and/orin the printing fluid itself. The printing fluid may comprise: a) asolvent for a material in the bulk powder; b) a solvent for a materialin the printing fluid; or c) a combination thereof.

Embodiments of the process of the invention include those wherein theprinting fluid comprises a solvent for: a) LEV; b) a binder in the bulkpowder; c) a binder in the printing fluid; d) LEV and a binder; or e) acombination thereof.

The printing fluid can comprise 55-95% wt, 60-85% wt or 65-75% wt ofwater or aqueous buffer.

The printing fluid can comprise 1-25% wt, 5-20% wt or 10-15% wt of atleast one organic solvent. A suitable organic solvent is alcohol.Suitable alcohols include ethanol, methanol, propanol, isopropanol, or acombination thereof. In some embodiments, the alcohol is ethanol. Insome embodiments, the solvent is isopropanol.

It should be understood, that compounds used in the art of pharmaceuticsgenerally serve a variety of functions or purposes. Thus, if a compoundnamed herein is mentioned only once or is used to define more than oneterm herein, its purpose or function should not be construed as beinglimited solely to that named purpose(s) or function(s).

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith tissues of human beings and animals and without excessive toxicity,irritation, allergic response, or any other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein a “derivative” is: a) a chemical substance that isrelated structurally to a first chemical substance and theoreticallyderivable from it; b) a compound that is formed from a similar firstcompound or a compound that can be imagined to arise from another firstcompound, if one atom of the first compound is replaced with anotheratom or group of atoms; c) a compound derived or obtained from a parentcompound and containing essential elements of the parent compound; or d)a chemical compound that may be produced from first compound of similarstructure in one or more steps.

The invention also provides a method of administering LEV to a subjectin need thereof. The method comprises: (a) providing a rapidlydispersing, non-compressed matrix dosage form as described herein, and(b) inserting the dosage form into a moisture-containing body cavity,such as the mouth, of a subject in need thereof, the moisture beingcapable of dissolving the binder and dispersing the dosage form within atime period ranging from about one to about ninety seconds, therebydispersing the dosage form in the body cavity. In some embodiments, themethod further comprises the step of administering the dosage form tothe subject with a sip (small volume) of fluid after the dosage form isplaced in the mouth.

A study was conducted to determine whether or not the sip volumeimpacted the pharmacokinetic parameters of LEV following oraladministration of a 3DP dosage form of the invention. Subjects weregiven the option to sip 30 ml or less of aqueous fluid when taking the3DP dosage form. There was no correlation observed between sip volumeand pharmacokinetic parameters observed. The sip volume ranged from 2-30ml with an average of about 13 ml.

The invention also provides a method of treating a disease, disorder orcondition that is therapeutically responsive to LEV, the methodcomprising: a) administering to a subject in need thereof athree-dimensionally printed orodispersible matrix as described herein oras made by the process described herein. The matrix comprises LEV, abulk powder, disintegrant and binder, and the matrix is dispersible in asmall volume of fluid. The dosage and administration regimens detailedin the package inserts for FDA approved products containing LEV, e.g.KEPPRA®, or as described herein can be followed for administering theinstant dosage form.

A study was conducted according to Example 7 to determine thebioabsorption of levetiracetam when administered orally in anorodispersible 3DP dosage form of the invention. It was found that the3DP product of the invention is equivalent to the KEPPRA® referenceproduct in terms of the bioavailability of LEV under fasting conditions.Moreover, the 3DP product only exhibits a food effect upon Cmax and Tmaxbut not upon overall systemic exposure, i.e. not upon AUC_(0-t) orAUC_(inf). Based upon the KEPPRA® label, these results are consistentwith the pharmacokinetics of KEPPRA® tablets administered in the fedstate, whereby the extent of absorption is not affected but the Cmax isdecreased by about 20% and the Tmax is extended by 1.5 hours

Dose efficiency (AUC/dose) is a measure of how well a drug is absorbedrelative to the dose of drug administered. The 3DP dosage form of theinvention provides efficient bioabsorption of LEV whether administeredin the fed or fasting state. The 3DP dosage form provides the followingpharmacokinetic parameters when administered orally to a subject.

3DP Dose C_(max) AUC_(0-t) AUC_(inf) (mg) (microg/ml) T_(max) (hr)(microg-hr/ml) (microg-hr/ml) 1000 23-43 or 0.15-1.0 or 227-340 or235-351 or (fasting) 13-53 or 0.15-1.5 or 170-397 or 176-410 or 10-600.12-1.7 160-425 160-450 1000 17-24 or   3-5 or 223-302 or 231-314 or(Fed) 14-27 or   2-5 or 183-342 or 190-355 or 10-35   2-6 170-380170-400 750 16-31 or 0.15-1.0 or 180-270 or 186-278 or (fasting)  9-37or 0.15-1.5 or 135-315 or 140-324 or  8-40 0.12-1.7 120-350 120-375 75012-17 or   3-5 or 177-239 or 183-249 or (Fed) 10-19 or   2-5 or 145-271or 150-282 or  8-25   2-6 130-300 125-320 500  9-16 or 0.15-1.0 or119-179 or 123-185 or (fasting)  5-20 or 0.15-1.5 or  90-209 or  93-216or  4-25 0.12-1.7  80-220  85-240 500  6-9 or   3-5 or 117-159 or122-165 or (Fed)  5-10 or   2-5 or  96-180 or 100-187 or  4-15   2-6 85-200  87-220 250  6-11 or 0.15-1.0 or  72-108 or  75-112 or (fasting) 3-14 or 0.15-1.5 or  54-127 or  56-131 or  3-18 0.12-1.7  45-150 47-160 250  4-6 or   3-5 or  71-96 or  74-100 or (Fed)  4-7 or   2-5 or 58-109 or  60-113 or  3-10   2-6  47-125  50-140

The dosage form of the invention provides a fed/fasted ratio for Cmax inthe range of 0.55 to 0.74 (or about 0.6-0.7), for Tmax in the range of 5to 21 (or about 5-13 or 5-10), for AUC_(0-t) in the range of 0.89 to0.98 and for AUC_(inf) in the range of 0.89 to 0.99.

The dosage form of the invention is substantially equivalent in rate andextent of absorption to the KEPPRA® tablet, as the latter is defined byNew Drug Application No. N021035 (see above), in particular whenadministered under fasting conditions. The dosage form providessubstantially linear dose proportionality for Cmax and AUC, such that alinear fit of Cmax or AUC versus the dose administered can becharacterized as having a correlation coefficient, R², of 0.95 to 1.0.The Cmax and AUC for the orodispersible dosage form are within 80-125%of the values achieved by the KEPPRA® immediate release tablet producton an equivalent dose basis.

In view of the above description and the examples below, one of ordinaryskill in the art will be able to practice the invention as claimedwithout undue experimentation. The foregoing will be better understoodwith reference to the following examples that detail certain proceduresfor the preparation of embodiments of the present invention. Allreferences made to these examples are for the purposes of illustration.The following examples should not be considered exhaustive, but merelyillustrative of only a few of the many embodiments contemplated by thepresent invention.

Example 1 Preparation of a Three-Dimensionally Printed OrodispersibleDosage Form

The following process is used to prepare a three-dimensionally printedorodispersible dosage form comprising a matrix comprising LEV. Theingredients for the printing fluid and the bulk powder are used in theamounts indicated below:

Printing fluid I-A I-B I-C I-D Water (% wt) 68.99-70.7 68.47-69.1266.89-67.95 66.5-71   Glycerin (% wt) 3.9-4   3.8-3.92 3.79-3.85 3.5-4  Isopropanol (% wt) 13.01-13.3  12.3-13.04 12.11-12.82   12-13.5 Tween 20(% wt) 1.95-2    1.9-1.96 1.89-1.92 0.5-2   Povidone (% wt) 9.76-10 8.5-9.8 8.51-9.61 8.5-10  Sucralose (% wt) 2 2-5 4-6 0-3 Monoammonium0.2-0.6 0-1 glycyrrhizinate (% wt) Magnasweet 100 Spearmint Flavor0.01-0.03 0.01-0.05 0-1 HD45 Natural Peppermint    0-0.38 0-1 FlavorHD29 Printing fluid I-E I-F I-G I-H Water (% wt) 65-72 65-70 Glycerin (%wt) 3.5-4   3.4-4.2 Isopropanol (% wt)   12-13.5 11-13 Tween 20 (% wt)1-2 1.5-2.5 Povidone (% wt) 8.5-10   8-10 Sucralose (% wt) >0-5  4-6Monoammonium glycyrrhizinate   0-0.6 0.1-0.8 (% wt) Magnasweet 100Spearmint Flavor HD45   0-0.2 >0-0.1 Natural Peppermint Flavor HD29  0-0.5 Bulk powder: II-A II-B II-C II-D II-E LEV (% wt) 75 75 65 6575-90  Avicel PH101 (% wt) 17.5 19.8 21.8 23.8 5-20 Mannitol (% wt) 12.510.5 Povidone (PVP K29/32) (% wt) 4.5 4.5 5-10 Sucralose (% wt) 2 1-3Monoammonium 0.5 0.5 glycyrrhizinate (% wt) Colloidal Silicon dioxide (%wt) 0.5 0.7 0.7 0.7 0.5 Bulk powder: II-F II-G II-H LEV (% wt) 65-75Avicel PH101 (% wt) 17.5-24   Mannitol (% wt) 10.5-12.5 Povidone (PVPK29/32) (% wt) 4-6 Sucralose (% wt) 1-3 Monoammonium glycyrrhizinate0.1-1   (% wt) Colloidal Silicon dioxide (% wt) 0.5-0.7 Antioxidant (%wt) 0.1-7  

An incremental layer of bulk powder of predetermined thickness is spreadonto a prior layer of powder, and printing fluid is applied to theincremental layer as droplets according to a predetermined saturationlevel, line spacing and printing fluid flowrate to bind the particlestherein. This two step process is completed until a matrix comprisingthe target amount of printed incremental layers.

Any three dimensional printer equipment assembly, known or mentionedherein, can be used; however, these exemplary formulations can be madewith a Coriolis Instrument (Dimatix/Spectra Technology Integration,model: Coriolis RP1). The printer is operated at a droplet size of 70-90picoliter, and resolution of 200-400 dpi or about 300 dpi by 900-1500dpi. Various different print patterns are used in the dosage form. Thespecified combination of printing fluid formulation and bulk powderformulation is used. A layer thickness of 0.008 to 0.011 inches or about0.25 to about 0.265 mm is used. A resolution of 300×1200 dpi, 300×1000dpi, 300×900 dpi, 400×900 dpi, 400×750 dpi, 400×675 dpi is used. Theprinting fluids I-A through I-D are used. Many different combinations ofthe printing fluids and bulk powder formulations are used. Some of theresulting matrices comprise the following ingredients.

III-A LEV (% wt) 60-70 Avicel PH101 (% wt) 20-25 Mannitol (% wt) 9.5-11 Povidone (PVP K29/32) (% wt) 1-2 Sucralose (% wt) 0.5-1.5 ColloidalSilicon dioxide (% wt) 0.5-1   Moisture (% wt) 0.3-4   Glycerin (% wt)0.1-1   Tween 20 (% wt) 0.1-0.5 Spearmint Flavor HD45  >0-0.2Monoammonium glycyrrhizinate 0.05-0.15 (% wt)

The printed matrix is separated from loose unprinted powder and theprinted matrix is dried by any suitable means to reduce the amount ofsolvent and moisture to a desired level, thereby producing the final 3DPorodispersible dosage form.

The dispersion time, surface texture (smoothness) and hardness of thedosage form are then determined.

Example 2 Rapidly Dispersing Wafers with Varying Architecture inDifferent Incremental Layers Preparation of a Taste-MaskedThree-Dimensionally Printed Orodispersible Dosage Forms with VaryingArchitecture Among Incremental Layers

The 3DP process described above is followed; however, it can beconducted in several different ways to prepare dosage forms of differentarchitecture varying in hardness and composition of incremental layers.The following processes provide a wafer having greater hardness in theupper and lower surfaces as compared to the hardness of the interiorportion of the wafer. This tactic helps create sections within a waferwith different mechanical properties. This approach is used to designwafers in which the composition of the top and bottom layers isdifferent from the middle layers. This design allows the wafers to havestronger top and bottom layers, thereby increasing hardness and reducingfriability, and a large middle portion with lower hardness, whichenables the wafer to disperse rapidly.

Method A:

In this process, the amount of binder deposited in different incrementallayers or within different predefined regions within the sameincremental layers is varied. The process of Example 3 is followed toprepare these wafers, except that the amount of binder, by way of theprinting fluid, deposited onto the powder is varied among theincremental powder layers by using printing fluids differing inconcentration of binder.

Method B:

The process of Example 3 is followed to prepare these wafers, exceptthat the amount of printing fluid deposited onto the powder is variedamong the incremental powder layers. The upper and lower incrementallayers receive a higher amount of printing fluid and the incrementallayers of the middle portion receive a lower amount of printing fluid.

Method C:

In this process, the printing pattern, employed for the upper and lowerincremental layers of the dosage form, is a solid pattern (FIG. 3A). Theprinting pattern for the middle portion of incremental layers is a grayscale (FIG. 3 B). Gray scale printing can range from about 20 to about90% or about 20 to about 80%.

Method D:

In this process, the printing pattern, employed for the upper and lowerincremental layers of the dosage form, is a solid pattern (FIG. 3A). Theprinting pattern for the middle portion of incremental layers is anannular/hollow high saturation printing with no printing in the areasurrounded by the annulus (FIG. 3C).

Method E:

In this process, the printing pattern, employed for the upper and lowerincremental layers of the dosage form, is a solid pattern (FIG. 3A). Theprinting pattern for the middle portion of incremental layers is acombination of interior gray scale printing surrounded by an exteriorhigh saturation printing (FIG. 3D).

Example 3 Characterization of Dosage Forms

The following procedures were used to characterize thethree-dimensionally printed solid porous orodispersible matrices.

Friability

The matrices are analyzed for their resistance to breaking using thetablet friability test (USP protocol <1216>). The test employs a VanKelfriabilator (model 45-2000, Varian, USA) equipped with a drum having thedimensions of 285 mm in diameter and 39 mm deep, which is rotated at 25rpm for 100 revolutions. A minimum number of 10 wafers are tumbled ateach revolution by a curved projection that extends from the middle ofthe drum to the outer wall. Thus, at each turn the tablets are caused toroll or slide and fall about 130 mm onto the drum or each other. Allloose powder is removed from the tablets and they are weightedcollectively before and after the 100 revolutions.

Surface Texture

The matrices are inspected visually with or without the aid of amicroscope. The surface texture analyzed to determine if it is rough orsmooth and whether the edges of indicia on the upper surface and theedges of the perimeter of the wafer are clean and sharp or rough andjagged.

The matrices exhibited smooth surfaces with clean and sharp edges.

Hardness

The matrices are analyzed for overall hardness as determined by a tabletbreaking force assay according to USP <127> (31^(st) edition) using a VK200 tablet hardness tester (Varian, US). The strength or hardness of thewafers is measured by a fracture test. A wafer is centered between thejaws of the tester and force is applied until the wafer fractures. Theload at fracture is returned in kiloponds (kp). A kilopond is a metricunit of force measurement with 1 kp being equivalent to 9.807 Newtons. Aminimum number of 6 wafers are tested.

The hardness of the dosage forms ranges from about 0.7 to about 5.3 kp,about 1.7 to about 5.1 kp, about 2.1 to about 5.2 kp, about 3 to about 6kp, about 1 to about 9 kp, or about 2.5 to about 5.3 kp.

Dispersion Time

The matrices are analyzed for dispersion time in aqueous fluid asfollows using a Texture Analyzer (TA HP, Texture Technologies, US)equipped with a 5 Kg load cell and a 1.0 inch diameter acrylic probe(Stable Micro Systems). The wafer is attached to the probe withdouble-sided adhesive tape. Under a constant 50 g force (Dor et al. inPharm. Dev. Technol. (2000), 5(4), 575-577; and El-Arini et al. inPharm. Dev. Technol. (2002), 7(3), 361-371), the wafer is immersed in 3ml of water at room temperature in a flat bottom aluminum weigh boat.The dispersion time test was conducted using the following parameters. Aminimum of 5 wafers was tested.

Test mode Compression Pre-test speed (mm/sec) 5 Test speed (mm/sec) 8Post-test speed (mm/sec) 10 Target mode Force Force (g) 50 Hold time(sec) 15 Trigger type Auto (force) Trigger force (g) 5 Water volume (ml)3

The dispersion time observed for the dosage forms is about 10 sec orless or about 5 sec or less.

Bulk Density

The bulk density of the matrix is determined by measuring the weight ofa wafer and dividing that value by the calculated volume of the wafer.The volume of a wafer is calculated by measuring its dimensions andusing the proper mathematical formula according to the shape of thewafer. For example, for a cylindrical wafer, the volume of which iscalculated using the form π*r²*H, wherein r is the radius of the waterand H is its height. A wafer weighing 0.5 g, having a height of 0.6 cmand a diameter of 1.1 cm, has a volume of about 0.57 cm³, and a bulkdensity of about 0.877 g/cm³, which is equivalent to about 877 mg/ml.

Dissolution of LEV

Dissolution testing is conducted according to the Guidance for Industry(Section 3.3.2; Waiver of In Vivo Bioavailability and BioequivalenceStudies for Immediate-Release Solid Oral Dosage Forms Based on aBiopharmaceutics Classification System. August 2000. Section IIIc, p 7).The method of USP <711> was followed. Dissolution is performed using aUSP Apparatus II (paddle) at 50 rpm using 900 mL of the followingdeaerated dissolution media: (1) 0.1N HCl; (2) 0.05 M sodium acetate, pH4.5 buffer and (3) 0.05M KH₂PO₄, pH 6.8 buffer at 37° C.

Example 4 In Vivo Evaluation of Three-Dimensionally PrintedOrodispersible Dosage Forms

This method is used to establish efficacy of the dosage form. Singledosage forms comprising LEV are administered twice daily to a subject at12-hour intervals. Administration is done by placing the dosage form inthe mouth of the subject and optionally administering a sip (5-20 ml, or2-30 ml) of fluid to the subject. Within a short period of time, thedosage form disperses in the subject's mouth. Alternatively, the dosageform is dispersed in a minimal amount of fluid and then administered tothe subject orally. The total daily dose of LEV will typically rangefrom about 500 to about 2000 mg divided over two doses. The subject'spharmacokinetic profile is determined using known methods in the art.The subject level of therapeutic response to the dosage form isdetermined using known methods in the art.

Example 5 HPLC/MS Analysis for LEV in Dosage Forms

The following procedures were used to analyze three-dimensionallyprinted solid porous orodispersible matrices and in support ofdrug-stability studies.

The following solutions were used.

Buffer: 20 mM ammonium acetate, pH 5.5

Mobile phase A (MPA): 95:5 Buffer:acetonitrile

Mobile phase B (MPB): Acetonitrile

Diluent: 95:5 water:acetonitrile

The HPLC conditions were as follows:

Column: Alltima C18 4.6×150 mm, 5 μm

Mobile phase A (MPA): 95:5 Buffer:acetonitrile

Mobile phase B (MPB): Acetonitrile

UV detection: 205 nm

Column temperature: 25° C.

Injection volume: 10 μL

Flow rate: 0.9 mL/min

Autosampler temperature: 5° C.

Samples were prepared by transferring approximately 380 mg of sample toa 50-mL volumetric flask with 30 mL of Diluent. The sample was sonicatedfor 10 minutes then filled to volume with Diluent. A portion wasfiltered through a 0.22 μm nylon filter, discarding the first 3-5 mL.

Mass spectrophotometry was conducted by directly infusing a sodiumformate solution into the mass spectrometer through the lock spray at100 μL/min using a syringe pump. The sodium formate peak at m/z158.9646126 was used for accurate mass analysis. The accurate masseswere used for elemental composition analysis using the MassLynxsoftware.

An impurity/degradant peak had a relative retention time (RRT) of 0.64using the client provided method. The peak had an observed, protonated,mono-isotopic mass of 185.1 Da. Accurate mass analysis and elementalcomposition analysis of the peak were consistent with oxo-levetiracetam.

Example 6 Evaluation of LEV Stability in 3DP Dosage Forms

The following procedures were used to identify the preferredantioxidant(s) suitable stabilizing LEV against oxidative degradation.

A powder blend containing the following ingredients in the amountsindicated was prepared.

Ingredient % (w/w) Levetiracetam, USP 65.0 Colloidal silicon dioxide, NF0.70 Microcrystalline cellulose, NF 23.8 Mannitol 50C, USP 10.5

A printing fluid containing the following ingredients in the amountsindicated was prepared.

Ingredient % (w/w) Function Povidone K29/32, USP 8.51 Binder, viscositymodifier Sucralose, NF 5.0 Sweetener N&A Spearmint flavor 0.03 FlavorantHD45 Glycerin, USP 3.8 Humectant Polysorbate 20, NF 1.9 SurfactantIsopropyl alcohol, USP 12.3 Solvent Purified water, USP 68.5 Solvent

The antioxidants evaluated are listed in the following table. Half ofthe amount of the IIG (Inactive Ingredient Guide) daily limit (mg)indicated in the table was used for each antioxidant since this wouldreach the limit when administered twice daily, which is the most commonfrequency of dosing immediate-release levetiracetam. For example, theamount of antioxidant would be “(IIG daily limit)/2” for a 1000 mgtablet administered twice daily. It should be understood that IIG limitsare periodically changed by regulatory agencies. Accordingly, the limitsspecified below should be considered approximations and not as absolutelimits to the amount of antioxidant that can be included in a dosageform.

Antioxidant IIG Daily Limit (mg) Ascorbic acid 28.44 Butylatedhydroxyanisole (BHA) 1 Butylated hydroxytoluene (BHT) 0.36 n-propylgallate 2 L-cysteine HCl 16.2 Sodium sulfite 0.65 Sodium bisulfite 0.65Alpha-tocopherol (Vit E) 1.34 EDTA 100 Sodium metabisulfite 8 Methionine5

The antioxidant was mixed with 6 mL of printing fluid. That mixture wasthen mixed with 30 g of powder blend to form a raw tablet composition,each of which was exposed to the following conditions: Condition 1—storecomposition at 70 C in tightly sealed glass jar; Condition 2—storecomposition at 50 C in loosely covered glass jar; and Condition 3—storecomposition at 40 C/75% RH in open glass jar.

The samples were subsequently analyzed by HPLC/MS and the identity oftwo key degradants was determined by comparison to standards. The keydegradants were levetiracetam acid and oxo-levetiracetam. Moreover, someof the raw compositions became colored (yellowing) and others did not.The data indicate that sodium bisulfite, sodium sulfite, Vitamin E,methionine, BHA and BHT provide improved stability against oxidativedegradation and against color formation. Sodium bisulfite, sodiumsulfite, BHA and BHT provided the best results under the testconditions. Other antioxidants tested provided lesser degrees ofprotection or no protection against oxidative degradation and colorformation.

Example 7 Determination of PK Parameters for LEV in Orodispersible 3DPDosage Forms

The following procedures were used to determine the PK parameters of theorodispersible 3DP dosage form of the invention and to compare them tothose of the commercial product KEPPRA film-coated tablets.

A single center, randomized, single dose, laboratory-blinded, 3-period,3-sequence crossover study was conducted. Thirty-two male and femalesubjects 18-50 yr of age and in good health were included. The subjectswere orally administered single doses of a 3DP dosage form containing1000 mg of LEV or a KEPPRA® tablet containing 1000 mg of LEV. The singledose was administered once-a-week for three weeks as follows, therebyproviding a 7-day wash-out period between doses:

-   -   Group I: single dose of 3DP dosage form administered in the        morning after a 10-hour overnight fast    -   Group II: single dose of KEPPA® tablet administered in the        morning after a 10-hour overnight fast    -   Group III: single dose of 3DP dosage form administered in the        morning after a 10-hour overnight fast and 30 min after the        start of a high-fat, high calorie breakfast

The plasma concentration of LEV was determined prior to and afteradministration of each dose. The food effect was determined by comparingthe C_(max), T_(max), AUC_(0-t) and AUC_(inf) obtained for the fastingand fed conditions. The following data provides a summary of the PKdata.

AUC_(inf) Dosage C_(max) AUC_(0-t) (microg- Form (microg/ml) T_(max)(hr) (microg-hr/ml) hr/ml) KEPPRA ® Mean: 30.48 Mean: 0.58 Mean: 274.9Mean: 284.3 (fasting) C.V.: 19.0 C.V.: 69.9 C.V.: 18.2 C.V.: 18 3DPMean: 33.27 Mean: 0.58 Mean: 283.69 Mean: 292.9 (fasting) C.V.: 30.1C.V.: 73.7 C.V.: 20 C.V.: 19.9 3DP Mean: 20.48 Mean: 4 Mean: 262.6 Mean:272.6 (Fed) C.V.: 16.3 C.V.: 21.6 C.V.: 15.1 C.V.: 15.2

It was found that the 3DP product of the invention is equivalent to theKEPPRA® reference product in terms of the bioavailability of LEV underfasting conditions. Moreover, the 3DP product only exhibits a foodeffect upon Cmax and Tmax but not upon overall systemic exposure, i.e.not upon AUC_(0-t) or AUC_(inf). These results are consistent with thepharmacokinetics of KEPPRA® tablets administered in the fed state(KEPPRA® label, NDA 021035).

As used herein, the term “about” or “approximately” are taken tomean±10%, ±5%, ±2.5% or ±1% of a specified valued. As used herein, theterm “substantially” is taken to mean “to a large degree” or “at least amajority of” or “more than 50% of”.

The above is a detailed description of particular embodiments of theinvention. It will be appreciated that, although specific embodiments ofthe invention have been described herein for purposes of illustration,various modifications may be made without departing from the spirit andscope of the invention. Accordingly, the invention is not limited exceptas by the appended claims. All of the embodiments disclosed and claimedherein can be made and executed without undue experimentation in lightof the present disclosure.

The invention claimed is:
 1. A rapidly dispersible solid dosage formcomprising a three-dimensionally printed bound matrix comprising 50-80%wt of levetiracetam (LEV), 3-35% wt of disintegrant and 0.5-20% wt ofbinder, wherein the matrix disperses in about 15 sec or less in a volumeof about 15 ml or less of water or saliva, wherein the matrix has ahardness of at least 2 kp.
 2. The dosage form of claim 1, wherein thebound matrix further comprises antioxidant.
 3. The dosage form of claim2, wherein the bound matrix comprises 0.005 to about 5.0% wt ofantioxidant.
 4. The dosage form of claim 1, wherein the bound matrixcomprises 0.1% or less of an oxidative degradant of LEV after beingstored at 21° C. for six months at 75% RH.
 5. The rapidly dispersiblesolid dosage form of claim 1, wherein the dosage form provides a Cmaxwithin the ranges listed below when respective doses of levetiracetamare administered to a subject in the fasting state Dose C_(max) (mg)(micrograms/ml) 1000 13-53  750 9-37 500 5-20 250 4-7. 


6. The dosage form of claim 5, wherein the dosage form provides a Tmaxwithin the range of 0.15-1.5 hours.
 7. The dosage form of claim 5,wherein the dosage form provides an AUC_(0-t) or an AUC_(inf) within theranges listed below Dose AUC_(0-t) AUC_(inf) (mg) (microg-hr/ml)(microg-hr/ml) 1000 170-397 176-410 750 135-315 140-324 500  90-209 93-216 250  54-127   56-131.


8. The rapidly dispersible solid dosage form of claim 1, wherein thedosage form provides a Cmax within the ranges listed below whenrespective doses of levetiracetam are administered to a subject in thefed state Dose C_(max) (mg) (microg/ml) 1000 14-27 750 10-19 500  5-10250  4-7.


9. The dosage form of claim 8, wherein the dosage form provides a Tmaxwithin the range of 2-5 hours.
 10. The dosage form of claim 8, whereinthe dosage form provides an AUC_(0-t) or an AUC_(inf) within the rangeslisted below Dose AUC_(0-t) AUC_(inf) (mg) (microg-hr/ml) (microg-hr/ml)1000 183-342 190-355 750 145-271 150-282 500  96-180 100-187 250  58-109 60-113.


11. The rapidly dispersible solid dosage form of claim 1, wherein thedosage form provides a fed/fasted ratio for Cmax, as measured inmicrograms/ml, in the range of 0.55 to 0.74 and for Tmax, as measured inhours, in the range of 5 to
 21. 12. The dosage form of claim 11, whereinthe dosage form provides a fed/fasted ratio, for AUC_(0-t), as measuredin microg-hr/ml, in the range of 0.89 to 0.98 and for AUC_(inf), asmeasured in microg-hr/ml, in the range of 0.89 to 0.99.
 13. The dosageform of claim 1, wherein the dosage form is equivalent in rate andextent of absorption to a KEPPRA® tablet, as defined by NDA No. N021035,in terms of C_(max), AUC_(0-t) or AUC_(inf).
 14. The dosage form ofclaim 1, wherein: a) the dosage form is not compressed; b) the boundmatrix is not compressed; c) the exterior of the bound matrix is harderthan the interior of the bound matrix; d) the dissolution time of LEV isslower than the dispersion time of the bound matrix when placed in anaqueous fluid; e) the bound matrix disperses in about 10 seconds or lesswhen placed in a small volume of aqueous fluid; f) at least 75% of theLEV dissolves in about 2 minutes or less when placed in an aqueousfluid; g) LEV is present in a form selected from the group consisting ofhydrate, hemi-hydrate, crystalline, amorphous, anhydrate or acombination thereof; h) the dosage form comprises not more than 10% wtand not less 0.1% moisture as determined by loss on drying at 120° C.;i) the hardness of the bound matrix is substantially uniform; j) thedosage form comprises one or more other medicaments; k) the bound matrixfurther comprises glycerin; l) the bound matrix further comprisesglycerin in an amount ranging from about 0.05%-3% wt; or m) at least 95%wt of LEV is dissolved in 5 minutes or less in 900 ml of aqueous mediaat pH 1.2, 4.5 or 6.8 in a USP paddle apparatus operating at 50 RPM. 15.The dosage form of claim 1, wherein the bound matrix further comprisesone or more surfactants, one or more antioxidants, glycerin andoptionally one or more of the following: one or more glidants, one ormore flavorants, one or more preservatives; the bound matrix comprisesparticles bound by binder and LEV; the bound matrix is porous andnon-compressed; and the bound matrix disperses in less than 15 sec in avolume of 10 ml of aqueous fluid.
 16. The dosage form of claim 15wherein: a) the at least one surfactant is present in an amount rangingfrom about 0.05 to about 1% wt based upon the final weight of the dosageform; b) the at least one antioxidant is present in an amount range fromabout 0.005 to about 5.0% wt based upon the final weight of the dosageform; c) the at least one glidant is present in an amount range fromabout 0.1 to about 2.0% wt, based upon the final weight of the dosageform; or d) the bound matrix comprises about 250 to about 1000 mg ofLEV.
 17. The dosage form of claim 1, wherein the dosage form has beenprepared by a three-dimensional printing process.
 18. The dosage form ofclaim 1, wherein the dosage form comprises the following ingredientsIngredient Amt (% wt) LEV 60-70 disintegrant 20-25 binder 10-15sweetener 0.5-2   glidant 0.1-1.5 glycerin 0.1-5   surfactant 0.05-1.5 flavor   0-0.5.


19. The dosage form according to claim 18, wherein the dosage formfurther comprises antioxidant.
 20. The dosage form of claim 3, wherein:a) the hardness of the bound matrix ranges from about 2 to about 6 kp orabout 3 to about 9 kp; b) the bound matrix disperses in 10 sec or lesswhen placed in 15 ml of water or saliva; c) binder is introduced intothe bound matrix by way of printing fluid used to form the matrix; d)binder is introduced into the bound matrix by way of bulk powder used toform the matrix; e) the bound matrix comprises about 250 mg to about1000 mg of LEV; f) the bound matrix comprises 15 to 50 printedincremental layers; g) the bound matrix comprises 15 to 50 printedincremental layers and the thickness of an incremental layer ranges from0.008 to 0.012 inches; or h) the bound matrix is porous andnon-compressed.
 21. The dosage form of claim 1, wherein the dosage formis preservative free.
 22. A method of treating a disease, condition ordisorder that is therapeutically responsive to levetiracetam comprisingadministering a dosage form of claim 1 one to three times daily to asubject in need thereof throughout a treatment period.
 23. The dosageform of claim 1, wherein the hardness is about 2 to about 6 kp or about3 to about 9 kp.
 24. A rapidly dispersible solid dosage form comprisinga three-dimensionally printed bound matrix comprising 50-80% wt oflevetiracetam, 3-35% wt of disintegrant and 0.5-20% wt of binder,wherein the matrix disperses in about 15 sec or less in a volume ofabout 15 ml or less of water or saliva, wherein the matrix has ahardness of at least 2 kp, and the dosage form provides a fed/fastedratio, for AUC_(0-t), as measured in microg-hr/ml, in the range of 0.89to 0.98 and for AUC_(inf), as measured in microg-hr/ml, in the range of0.89 to 0.99.
 25. A rapidly dispersible solid dosage form comprising athree-dimensionally printed bound matrix comprising 50-80% wt oflevetiracetam, 3-35% wt of disintegrant and 0.5-20% wt of binder,wherein the matrix disperses in about 15 sec or less in a volume ofabout 15 ml or less of water or saliva, wherein the matrix has ahardness of at least 2 kp, and the bound matrix is porous andnon-compressed.
 26. A rapidly dispersible solid dosage form comprising athree-dimensionally printed bound matrix comprising 50-80% wt oflevetiracetam, 3-35% wt of disintegrant and 0.5-20% wt of binder,wherein the matrix disperses in about 15 sec or less in a volume ofabout 15 ml or less of water or saliva, wherein the matrix has ahardness of at least 2 kp, and the bound matrix comprises about 250 toabout 1000 mg of levetiracetam.